Article
Iron Death Regulatory Network: Expression Characterization and Prognostic Correlation Study of ARL6IP1 in Colorectal Cancer
Downloads
Download

This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright
The authors shall retain the copyright of their work but allow the Publisher to publish, copy, distribute, and convey the work.
License
Trends in Immunotherapy (TI) publishes accepted manuscripts under Creative Commons Attribution 4.0 International (CC BY 4.0). Authors who submit their papers for publication by TI agree to have the CC BY 4.0 license applied to their work, and that anyone is allowed to reuse the article or part of it free of charge for any purpose, including commercial use. As long as the author and original source are properly cited, anyone may copy, redistribute, reuse, and transform the content.
This study leveraged publicly available databases, including The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), to investigate the expression patterns of ARL6IP1 in colorectal cancer (CRC) and its prognostic relevance. The results demonstrated that reduced ARL6IP1 expression is strongly associated with poorer overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) in CRC patients, establishing ARL6IP1 as an independent prognostic marker for CRC. Further analyses using Gene Set Enrichment Analysis (GSEA) and Protein-Protein Interaction (PPI) network investigations indicated that low ARL6IP1 expression is enriched in cancer-related signaling pathways, suggesting its involvement in CRC pathogenesis through the ferroptosis mechanism. Additionally, the study uncovered a correlation between ARL6IP1 expression and immune cell infiltration within the tumor microenvironment (TME), particularly immunosuppressive cell populations such as regulatory T cells (Tregs) and M2-type macrophages. Diminished ARL6IP1 levels may promote the development of an immunosuppressive TME, thereby aiding tumor immune evasion. Collectively, these findings highlight ARL6IP1 as a critical ferroptosis-related gene that may significantly influence CRC progression and immune escape, offering a potential target for prognostic evaluation and therapeutic intervention in CRC. This study aims to investigate the expression patterns of ARL6IP1 in colorectal cancer (CRC) and its prognostic significance, as well as its correlation with immune cell infiltration in the tumor microenvironment. By leveraging publicly available databases, we sought to determine whether ARL6IP1 could serve as a potential prognostic biomarker and therapeutic target for CRC.
Keywords:
Colorectal Cancer (CRC); ARL6IP1; Ferroptosis; Tumor Immune Microenvironment (TME); prognostic BiomarkersReferences
- Acar, D. Identification of novel genetic gains and losses in early age of onset breast cancer by array comparative genomic hybridization. Cancer Genet. 2009, 202, 11–20.
- Guo, F.; Li, Y.; Liu, Y.; et al. ARL6IP1 mediates cisplatin-induced apoptosis in CaSki cervical cancer cells. Oncol. Rep. 2010, 23, 1449–1455.
- Akiduki, S.; Ikemoto, M.J.J. Modulation of the neural glutamate transporter EAAC1 by the addicsin-interacting protein ARL6IP1. J. Biol. Chem. 2008, 283, 31323–31332.
- Chukhrova, A.L.; Akimova, I.A.; Shchagina, O.A.; et al. A new case of infantile‐onset hereditary spastic paraplegia with complicated phenotype (SPG61) in a consanguineous Russian family. J. Neurol. 2019, 26, 318–321.
- Battaglia, A.M.; Chirillo, R.; Aversa, I.; et al. Ferroptosis and cancer: mitochondria meet the “iron maiden” cell death. Cancers 2020, 9, 1505.
- Ding, K.; Liu, X.; Wang, L.; et al. Targeting JWA for cancer therapy: functions, mechanisms and drug discovery. Cancers 2022, 14, 4655.
- Bishayee, K.; Habib, K.; Nazim, U.M.; et al. RNA binding protein HuD promotes autophagy and tumor stress survival by suppressing mTORC1 activity and augmenting ARL6IP1 levels. J. Exp. Clin. Cancer Res. 2022, 41, 1–18.
- Li, L.; Zhao, J.; Wang, Y.; et al. Integration of machine learning and experimental validation to identify the prognostic signature related to diverse programmed cell deaths in breast cancer. Cancers 2025, 14, 1505934.
- Bordini, J.; Morisi, F.; Elia, A.R.; et al. Iron induces cell death and strengthens the efficacy of antiandrogen therapy in prostate cancer models. Cancers 2020, 26, 6387–6398.
- Deng, H.-S.; Xu, L.S.; Ni, H.D.; et al. Proteomic profiling reveals Arl6ip-1 as a candidate target in cancer-induced bone pain rat model after oxycodone treatment. Proteomics 2019, 699, 151–159.
- Bryant, D.; Barberan-Martin, S.; Maeshima, R.; et al. RNA Therapy for Oncogenic NRAS-Driven Nevi Induces Apoptosis. Cancer Res. 2025, 145, 122–134.e11.
- Hu, Y.; Liu, S.; Liu, W.; et al. Bioinformatics analysis of genes related to iron death in diabetic nephropathy through network and pathway levels based approaches. PLOS One 2021, 16, e0259436.
- Carvalho, A.S.; Baeta, H.; Silva, B.C.; et al. Extra-cellular vesicles carry proteome of cancer hallmarks. Cancer Cell Int. 2020, 25, 398–436.
- Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; et al. Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death. Cell 2012, 149, 1060–1072.
- Guo, F.; Liu, Y.; Li, Y.; et al. Inhibition of ADP-ribosylation factor-like 6 interacting protein 1 suppresses proliferation and reduces tumor cell invasion in CaSki human cervical cancer cells. Mol. Biol. Rep. 2010, 37, 3819–3825.
- Concilli, M.; Iacobacci, S.; Chesi, G.; et al. A systems biology approach reveals new endoplasmic reticulum-associated targets for the correction of the ATP7B mutant causing Wilson disease. Mol. Aspects Med. 2016, 8, 920–930.
- Kuroda, M.; Funasaki, S.; Saitoh, T.; et al. Determination of topological structure of ARL6ip1 in cells: identification of the essential binding region of ARL6ip1 for conophylline. J. Biol. Chem. 2013, 587, 3656–3660.
- Stevens, R.G.; Graubard, B.I.; Micozzi, M.S.; et al. Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int. J. Cancer 1994, 56, 364–369.
- Kamble, K.; Kumar, U.; Aahra, H.; et al. A novel ER stress regulator ARL6IP5 induces reticulophagy to ameliorate the prion burden. Cell Death Discov. 2024, 1–21.
- Ninmer, E.; Spaeder, M.; Peroutka, C.; et al. Necrotizing enterocolitis totalis complicates an infantile presentation of ARL6IP1-related spastic paraplegia 61. Pediatr. Surg. Case Rep. 2021, 75, 102063.
- Louandre, C.; Ezzoukhry, Z.; Godin, C.; et al. Iron‐dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Free Radic. Biol. Med. 2013, 133, 1732–1742.
- Yu, Z.; Persson, H.L.; Eaton, J.W.; et al. Intralysosomal iron: a major determinant of oxidant-induced cell death. Free Radic. Biol. Med. 2003, 34, 1243–1252.
- Li, Y.; Du, Y., Zhou, Y.; et al. Iron and copper: critical executioners of ferroptosis, cuproptosis and other forms of cell death. Front. Oncol. 2023, 21, 327.
- Lin, Z.; Yang, S., Zhou, Y.; et al. OLFM4 depletion sensitizes gallbladder cancer cells to cisplatin through the ARL6IP1/caspase-3 axis. Cancers 2022, 16, 101331.
- Lehrer, S.; Rheinstein, P.H. EARS2 significantly coexpresses with PALB2 in breast and pancreatic cancer. Cancer Treat. Commun. 2022, 32, 100595.
- Persson, H.L.; Yu, Z., Tirosh, O.; et al. Prevention of oxidant-induced cell death by lysosomotropic iron chelators. Free Radic. Biol. Med. 2003, 34, 1295–1305.
- Liu, N.; Liu, X., Zhou, N.; et al. Gene expression profiling and bioinformatics analysis of gastric carcinoma. Oncol. Lett. 2014, 96, 361–366.
- Huang, G.; Ma, L., Shen, L.; et al. MIF/SCL3A2 depletion inhibits the proliferation and metastasis of colorectal cancer cells via the AKT/GSK‐3β pathway and cell iron death. Cancers 2022, 26, 3410–3422.
- Li, S.; Huang, Y. Ferroptosis: an iron-dependent cell death form linking metabolism, diseases, immune cell and targeted therapy. Cancers 2022, 24, 1–12.
- Huang, H.-Y.; Liu, J.-T.; Yan, H.-Y.; et al. ARL6IP1 plays a role in proliferation during zebrafish retinogenesis. Cell Tissue Res. 2012, 196, 161–174.
- Maddirevula, S.; Alzahrani, F., Al-Owain, M.; et al. Autozygome and high throughput confirmation of disease genes candidacy. Genet. Med. 2019, 21, 736–742.
- Lim, J.H.; Kang, H.M., Kim, D.H.; et al. ARL6IP1 gene delivery reduces neuroinflammation and neurodegenerative pathology in hereditary spastic paraplegia model. Cell Death Dis. 2023, 221, e20230367.
- Sasazawa, Y.; Sato, N.; Umezawa, K.; et al. Conophylline protects cells in cellular models of neurodegenerative diseases by inducing mammalian target of rapamycin (mTOR)-independent autophagy. J. Biol. Chem. 2015, 290, 6168–6178.
- Lin, Y.; Karnan, S.; Ito, H.; et al. Suppression of ARL6ip1 inhibits malignant phenotypes of human colorectal cancer cells in vivo and in situ. Cancer Sci. 2024, 84, 4683–4683.
- Tang, R.; Cui, H.; Miao, P.; et al. Novel common target genes for breast cancer and colorectal cancer: A mendelian randomization and spatial transcriptomics study. Cancer Res. 2024, 28, 2459–2470.
- Lin, Y.; Sivasundaram, K.; Kojima, S.; et al. Cancer Science. Wiley: Hoboken, NJ, USA. 2024; p. 1259.
- Zhang, W.; Jin, J.; Cao, C.W.; et al. Combined treatment of polygonatum and Scutellaria baicalensis suppresses lung cancer cell proliferation through inducing ferroptosis. Cancers. 2023, 3, 100482.
- Terman, A.; Kurz, T. Lysosomal Iron, Iron Chelation, and Cell Death. Antioxid. Redox Signal. 2012, 18, 888–898.
- Yamamoto, Y.; Yoshida, A.; Miyazaki, N.; et al. ARL6IP1 has the ability to shape the mammalian ER membrane in a reticulon-like fashion. J. Biol. Chem. 2014, 458, 69–79.
- Wang, J.; Che, F., Zhao, Y.; et al. The Prognostic and Therapeutic Roles of ARL-6 Gene in Hepatocellular Carcinoma. Cancers 2024, 21, 207.